Non-random retention of protein-coding overlapping genes in Metazoa

Abstract

BackgroundAlthough the overlap of transcriptional units occurs frequently in eukaryotic genomes, its evolutionary and biological significance remains largely unclear. Here we report a comparative analysis of overlaps between genes coding for well-annotated proteins in five metazoan genomes (human, mouse, zebrafish, fruit fly and worm).ResultsFor all analyzed species the observed number of overlapping genes is always lower than expected assuming functional neutrality, suggesting that gene overlap is negatively selected. The comparison to the random distribution also shows that retained overlaps do not exhibit random features: antiparallel overlaps are significantly enriched, while overlaps lying on the same strand and those involving coding sequences are highly underrepresented. We confirm that overlap is mostly species-specific and provide evidence that it frequently originates through the acquisition of terminal, non-coding exons. Finally, we show that overlapping genes tend to be significantly co-expressed in a breast cancer cDNA library obtained by 454 deep sequencing, and that different overlap types display different patterns of reciprocal expression.ConclusionOur data suggest that overlap between protein-coding genes is selected against in Metazoa. However, when retained it may be used as a species-specific mechanism for the reciprocal regulation of neighboring genes. The tendency of overlaps to involve non-coding regions of the genes leads to the speculation that the advantages achieved by an overlapping arrangement may be optimized by evolving regulatory non-coding transcripts.

Successful COG8 and PDF overlap is mediated by alterations in splicing and polyadenylation signals

“…The observation that the transcribed sequences of some genes overlap in humans and other eukaryotes (Makalowska et al 2005;Sanna et al 2008;Solda et al 2008) might seem unexpected in light of the fact that the great majority of the genomes is composed of gene-poor regions. This type of arrangement is more frequently associated with viral (Hughes et al 2001;Pavesi 2006;Sabath et al 2009), bacterial (Sabath et al 2008;Sakharkar et al 2005) and compact eukaryotic genomes (Williams et al 2005), wherein it is assumed to have evolved in a way to overcome space constrains.…”

“…Although studies of complementary strand overlapping genes are common (Dan et al 2002;Shintani et al 1999;Zhou and Blumberg 2003), little is known about the mechanistic and evolutionary steps that ultimately result in co-directional (same-strand) overlapping genes in eukaryotes (Sanna et al 2008;Solda et al 2008). In order to address this issue, we studied a particular case of codirectional overlapping genes in humans, COG8 and PDF, two functionally relevant genes that overlap in the human chromosomal region 16q22.1.…”

“…Less frequently, two genes share the same-strand, forming co-directional overlapping gene pairs (Sanna et al 2008). Further classifications are based on the complete or partial sequence overlap (reviewed in (Solda et al 2008)). …”

Alpha T-catenin (CTNNA3): a gene in the hand is worth two in the nest

“…Nested genes are totally embedded within their host gene and may be transcribed in the same or the opposite direction to their host [26]. It is proposed that they have emerged by the insertion of a DNA sequence, which arose by gene duplication or retrotransposition, into an intron of a pre-existing gene.…”

“…This is anticipated to occur when the products of the gene partners have different functions [30]. Moreover, recent research has shown that overlapping genes are four times more likely to be co-expressed than expected by random probability, lending credence to the functional co-regulation hypothesis [26].…”